Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials

Abstract

Background: Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder.

Methods: We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort.

Findings: We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days).

Interpretation: We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials.

Funding: National Institutes of Health.

Conflict of interest statement

Conflicts of Interest: Dr. Calfee reports grants from NIH/NHLBI during the conduct of the study; grants from Glaxo Smith Kline, personal fees from Cerus Corp, outside the submitted work. Dr. Delucchi has nothing to disclose. Dr. Thompson reports grants from National Institutes of Health during the conduct of the study. Dr. Parsons has nothing to disclose. Dr. Ware has nothing to disclose. Dr. Matthay reports grants from NHLBI during the conduct of the study; grants from GlaxoSmithKline, other from RocheGenetec, personal fees from Cerus Inc, other from French Society of Intensive Care, outside the submitted work.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Flow diagram of patient inclusion in the first (ARMA) cohort and second (ALVEOLI) cohort.

Figure 2

Differences in the standardized values of each variable by phenotype on the y-axis, with the individual continuous variables along the x-axis, for the ARMA cohort (Figure 2A) and the ALVEOLI cohort (Figure 2B). The variables are sorted based on the degree of separation between the classes from maximum positive separation on the left (i.e. Phenotype 2 higher than Phenotype 1) to maximum negative separation on the right (i.e. Phenotype 2 lower than Phenotype 1). Variable standardization, in which all means are scaled to zero and standard deviations to one, is described in the Supplementary Methods; a value of +1 for the standardized variable signifies that the mean value for a given phenotype was one standard deviation higher than the mean value in the cohort as a whole. Abbreviations: IL = interleukin; TNFr1 = tumor necrosis factor receptor-1; PAI-1 = plasminogen activator inhibitor-1; MinVent = total minute ventilation; ICAM-1 = intercellular adhesion molecule-1; MAP = mean airway pressure; VWF = von Willebrand Factor; Creat = creatinine; Resp Rate = respiratory rate; Tbili = total bilirubin; PEEP = positive end expiratory pressure; Temp = temperature in Celsius; Hct = hematocrit; Urine = urine output over prior 24h; SP-D = surfactant protein D; BMI = body mass index; TV = tidal volume; Gluc = glucose; SBP = systolic blood pressure; ProtC = Protein C; Bicarb = bicarbonate; Aspir = aspiration; Pneum = pneumonia.

Figure 3

Figure 3A. Differences in categorical variables based on phenotype assignment in the ARMA cohort; p=0.007 for comparison of gender, p